SUMMARY The growing prevalence of obesity and associated type II diabetes is a major health concern, particularly among children. Maternal obesity represents a developmental risk factor that contributes to metabolic perturbations in the offspring. Recent data from our lab indicate that maternal obesity is associated with abnormally high levels of leptin in the embryo, but whether this pathological hyperleptinemia contributes to the metabolic malprogramming of the developing embryos remains largely unknown. Similarly, the neurobiological mechanisms underlying the detrimental effects of maternal diabetes on glucose homeostasis remain poorly understood. The autonomic nervous system plays a critical role in glucose metabolism through both its sympathetic and parasympathetic branches. We recently found an unanticipated role for prenatal leptin in the development of cholinergic projections to pancreatic islets and that this developmental effect has an impact on adult glucose homeostasis. The overall hypothesis of this proposal is that maternal obesity predisposes the offspring to diabetes by disrupting the development of hindbrain cholinergicpancreas circuits. We also hypothesize that leptin signaling in cholinergic neurons plays an important role in the nutritional malprogramming of glucose homeostasis. Our multidisciplinary approach incorporates a complementary set of genetic, optogenetic, axonal labeling, electrophysiological, and physiological tools to address the following aims: Specific Aim 1. We will use viral axonal labeling and immunohistochemical experiments to study the development of hindbrain cholinergic innervation of pancreatic b cells in a context of maternal obesity. We will also use optogenetic approaches to test if hindbrain cholinergicpancreas circuits are altered in animals exposed to maternal obesity. Specific Aim 2. We will systematically examine leptin levels in embryos and pups born to obese dams. We will then perform immunohistochemical labeling (pSTAT3 and pERK), slice electrophysiological recordings (measuring neuronal excitability, currents and synaptic inputs), and in vitro explant cultures to test the hypothesis that maternal obesity disrupts the neurophysiological, intracellular, and neurotrophic response of hindbrain cholinergic neurons to leptin in the offspring. Particular attention will be paid to the response of hindbrain cholinergic neurons innervating the pancreas. Specific Aim 3. Finally, we will expose dams carrying mice with genetic deletion of leptin receptor specifically in cholinergic neurons to a high fat/high sucrose diet to explore the importance of cholinergic leptin receptor signaling in mediating the detrimental effects of maternal obesity on the development of parasympathetic projections to pancreatic islets and glucose regulation. Completion of these aims will advance our understanding of how maternal obesity programs in the offspring essential components of neural systems required to maintain glucose homeostasis and may identify novel biomarkers and therapeutic targets.